U.S. patent application number 09/907909 was filed with the patent office on 2002-05-02 for cis-substituted aminocyclopropane derivative.
This patent application is currently assigned to DAIICHI PHARMACEUTICAL CO., LTD.. Invention is credited to Ishida, Yohhei, Kimura, Youichi, Takahashi, Hisashi, Takemura, Makoto.
Application Number | 20020052502 09/907909 |
Document ID | / |
Family ID | 16127021 |
Filed Date | 2002-05-02 |
United States Patent
Application |
20020052502 |
Kind Code |
A1 |
Takemura, Makoto ; et
al. |
May 2, 2002 |
Cis-substituted aminocyclopropane derivative
Abstract
The present invention relates to an antimicrobial compound
having high safety as well as potent antimicrobial activity on a
broad range of microorganisms represented by the following formula:
1
Inventors: |
Takemura, Makoto; (Tokyo,
JP) ; Kimura, Youichi; (Tokyo, JP) ;
Takahashi, Hisashi; (Tokyo, JP) ; Ishida, Yohhei;
(Tokyo, JP) |
Correspondence
Address: |
SUGHRUE MION ZINN MACPEAK & SEAS, PLLC
2100 Pennsylvania Avenue, NW
Washington
DC
20037-3213
US
|
Assignee: |
DAIICHI PHARMACEUTICAL CO.,
LTD.
|
Family ID: |
16127021 |
Appl. No.: |
09/907909 |
Filed: |
July 19, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09907909 |
Jul 19, 2001 |
|
|
|
09214433 |
Jan 6, 1999 |
|
|
|
Current U.S.
Class: |
546/123 ;
546/156 |
Current CPC
Class: |
A61K 31/4709 20130101;
C07D 207/26 20130101; A61K 31/4375 20130101; Y02A 50/30 20180101;
C07D 207/24 20130101; A61P 31/04 20180101; C07D 401/04
20130101 |
Class at
Publication: |
546/123 ;
546/156; 514/210.21; 514/300; 514/312 |
International
Class: |
A61K 031/4745; A61K
031/4709; C07D 471/02; C07D 41/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 12, 1996 |
JP |
HEI-8-182939 |
Claims
1. A compound represented by formula (I): 28wherein R.sup.1 and
R.sup.2 each independently represents a hydrogen atom or an alkyl
group having 1 to 6 carbon atoms which may be substituted with one
or more substituents selected from the group consisting of a
hydroxyl group, a halogen atom, an alkylthio group having 1 to 6
carbon atoms, and an alkyloxy group having 1 to 6 carbon atoms; n
represents an integer of 1 to 3; Q represents a partial structure
having formula: 29wherein R.sup.3 represents an alkyl group having
1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a
halogenoalkyl group having 1 to 6 carbon atoms, a substituted or
unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a
substituted or unsubstituted aryl group, a substituted or
unsubstituted heteroaryl group, an alkoxyl group having 1 to 6
carbon atoms, or an alkylamino group having 1 to 6 carbon atoms;
R.sup.4 represents a hydrogen atom or an alkylthio group having 1
to 6 carbon atoms; R.sup.3 and R.sup.4 may be taken together with
part of the mother skeleton to which they are bonded to form a
cyclic structure that may contain a sulfur atom as a ring
constituting atom and/or may be substituted with an alkyl group
having 1 to 6 carbon atoms; R.sup.5 represents a hydrogen atom, an
amino group, a hydroxyl group, a thiol group, a halogenomethyl
group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group
having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon
atoms or an alkoxyl group having 1 to 6 carbon atoms, in which the
amino group may be substituted with one or more substituents
selected from the group consisting of a formyl group, an alkyl
group having 1 to 6 carbon atoms, and an acyl group having 2 to 5
carbon atoms; X.sup.1 represents a halogen atom or a hydrogen atom;
and A represents a nitrogen atom or a partial structure represented
by formula (II): 30wherein X.sup.2 represents a hydrogen atom, an
amino group, a halogen atom, a cyano group, a halogenomethyl group,
a halogenomethoxyl group, an alkyl group having 1 to 6 carbon
atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl
group having 2 to 6 carbon atoms, or an alkoxyl group having 1 to 6
carbon atoms, in which the amino group may be substituted with one
or more substituents selected from the group consisting of a formyl
group, an alkyl group having 1 to 6 carbon atoms and an acyl group
having 2 to 5 carbon atoms; and X.sup.2 and R.sup.3 may be taken
together with part of the mother skeleton to which they are bonded
to form a cyclic structure that may contain an oxygen atom, a
nitrogen atom or a sulfur atom as a ring constituting atom and/or
may be substituted with an alkyl group having 1 to 6 carbon atoms;
and Y represents a hydrogen atom, a phenyl group, an acetoxymethyl
group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a
choline group, a dimethylaminoethyl group, a 5-indanyl group, a
phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmet- hyl group,
a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon
atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or a
phenylalkyl group having 1 to 6 carbon atoms in the alkyl moiety
thereof; and the two substituents on the cyclopropane ring, 31are
in a cis-configuration, or a salt or hydrate thereof or a hydrate
of the salt.
2. A compound according to claim 1, wherein Q in formula (I) is a
partial structure represented by formula: 32wherein R.sup.3,
R.sup.4, R.sup.5, X.sup.1, X.sup.2, and Y are as defined above, or
a salt or hydrate thereof or a hydrate of the salt.
3. A compound according to claim 1 or 2, wherein Q in formula (I)
is
a6-carboxy-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,-
4]benzoxazin-10-yl group, or a salt or hydrate thereof or a hydrate
of the salt.
4. A compound according to claim 1 or 2, wherein Q in formula (I)
is a
8-amino-6-carboxy-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-
-de][1,4]benzoxazin-10-yl group, or a salt or hydrate thereof or a
hydrate of the salt.
5. A compound according to claim 1 or 2, wherein Q in formula (I)
is a
5-amino-3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-
-8-methoxyl-4-oxoquinolin-7-yl group, or a salt or hydrate thereof
or a hydrate of the salt.
6. A compound according to claim 1 or 2, wherein Q in formula (I)
is a
5-amino-3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-
-8-methyl-4-oxoquinolin-7-yl group, or a salt or hydrate thereof or
a hydrate of the salt.
7. A compound according to claim 1 or 2, wherein Q in formula (I)
is a
3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-metho-
xyl-4-oxoquinolin-7-yl group, or a salt or hydrate thereof or a
hydrate of the salt.
8. A compound according to claim 1, 2, 3, 4, 5, 6 or 7, wherein n
in formula (I) is 2, or a salt or hydrate thereof or a hydrate of
the salt.
9. A compound according to claim 1, 2, 3, 4, 5, 6, 7 or 8, wherein
both R.sup.1 and R.sup.2 in formula (I) are a hydrogen atom, or a
salt or hydrate thereof or a hydrate of the salt.
10. A compound according to claim 1, 2, 8 or 9, wherein R.sup.3 in
formula (I) is a halogenocyclopropyl group, or a salt or hydrate
thereof or a hydrate of the salt.
11. A compound according to claim 1, 2, 8 or 9, wherein R.sup.3 in
formula (I) is a 1,2-cis-2-halogenocyclopropyl group, or a salt or
hydrate thereof or a hydrate of the salt.
12. A compound according to claim 1, 2, 8, 9, 10 or 11, wherein
R.sup.3 in formula (I) is a stereochemically pure substituent, or a
salt or hydrate thereof or a hydrate of the salt.
13. A compound according to claim 1, 2, 8 or 9, wherein R.sup.3 in
formula (I) is a (1R,2S)-2-halogenocyclopropyl group, or a salt or
hydrate thereof or a hydrate of the salt.
14. A compound according to claim 1, 2, 8, 9, 10 or 11, wherein
R.sup.3 in formula (I) is a (1R,2S)-2-fluorocyclopropyl group, or a
salt or hydrate thereof or a hydrate of the salt.
15. A compound according to claim 1, 2, 8, 9, 10, 11, 12, 13 or 14,
wherein X.sup.1 in formula (I) is a halogen atom, or a salt or
hydrate thereof or a hydrate of the salt.
16. A compound according to claim 1, 2, 8, 9, 10, 11, 12, 13, 14 or
15, wherein X.sup.1 in formula (I) is a fluorine atom, or a salt or
hydrate thereof or a hydrate of the salt.
17. A compound according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15 or 16, wherein the compound of formula (I) is a
stereochemically pure compound, or a salt or hydrate thereof or a
hydrate of the salt.
18.
5-Amino-7-{3-[(1S,2S)-2-aminocyclopropyl]-1-pyrrolidinyl}-6-fluoro-1-[-
(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxy-
lic acid or a salt or hydrate thereof or a hydrate of the salt.
19. A drug containing any of the compounds described in claims 1 to
18, hydrates thereof, salts thereof, and hydrates of the salts as
an active ingredient.
20. An antimicrobial agent containing any of the compounds
described in claims 1 to 18, hydrates thereof, salts thereof, and
hydrates of the salts as an active ingredient.
21. A compound represented by formula (VI): 33wherein R.sup.1 and
R.sup.2 each independently represents a hydrogen atom or an alkyl
group having 1 to 6 carbon atoms which may be substituted with one
or more substituents selected from the group consisting of a
hydroxyl group, a halogen atom, an alkylthio group having 1 to 6
carbon atoms, and an alkyloxy group having 1 to 6 carbon atoms; one
of R.sup.1 and R.sup.2 may be a protective group for amino group; n
represents an integer of 1 to 3; Q' represents a hydrogen atom or a
protective group for amino group; and the two substituents on the
cyclopropane ring, 34are in a cis-configuration; or a salt or
hydrate thereof or a hydrate of the salt.
22. A compound according to claim 21, wherein the protective group
for amino group is selected from the group consisting of an
alkoxylcarbonyl group, an aralkyloxycarbonyl group, an acyl group,
an alkyl group, an aralkyl group, and a substituted silyl group, or
a salt or hydrate thereof or a hydrate of the salt.
23. A compound according to claim 21 or 22, wherein the protective
group for amino group is selected from the group consisting of a
t-butoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a
benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a
p-nitrobenzyloxycarbonyl group, an acetyl group, a methoxyacetyl
group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl
group, a formyl group, a benzoyl group, a t-butyl group, a benzyl
group, a p-nitrobenzyl group, a p-methoxybenzyl group, a
triphenylmethyl group, a methoxymethyl group, a t-butoxymethyl
group, a tetrahydropyranyl group, a 2,2,2-trichloroethoxymethyl
group, a trimethylsilyl group, an isopropyldimethylsilyl group, a
t-butyldimethylsilyl group, a tribenzylsilyl group, and a
t-butyldiphenylsilyl group, or a salt or hydrate thereof or a
hydrate of the salt.
24. A compound according to claim 21, 22 or 23, wherein Q' and one
of R.sup.1 and R.sup.2 are different protective group for amino
groups, or a salt or hydrate thereof or a hydrate of the salt.
25. A compound according to claim 21, 22, 23 or 24, wherein the
compound of formula (VI) is a stereochemically pure compound, or a
salt or hydrate thereof or a hydrate of the salt.
26.
1-Benzyloxycarbonyl-3-[(1S,2S)-2-t-butoxycarbonylaminocyclopropyl]pyrr-
olidine.
Description
TECHNICAL FIELD
[0001] This invention relates to an antimicrobial compound useful
as a drug for humans, animals or fishes or an antimicrobial
preservative and an antimicrobial agent or preparation containing
the same.
BACKGROUND ART
[0002] Since the discovery of Norfloxacin, improvements have been
added to synthetic quinolone antimicrobial agents in antimicrobial
activity and in pharmacokinatics, and many compounds have been
launched for clinical use as a chemotherapeutic agent effective on
all most all systemic infectious diseases.
[0003] However, low sensitive bacteria resistant to the synthetic
quinolone antimicrobial agents have recently been increasing in the
clinical field. For example, bacteria resistant to drugs other than
synthetic quinolone antimicrobial agents have come to acquire
resistance to synthetic quinolone antimicrobial agents, as
exemplified by Staphylococcus aureaus insensitive to .beta.-lactam
antibiotics (MRSA). Therefore, more effective drugs have been
keenly demanded in the field of clinics.
[0004] Further, it has been revealed that synthetic quinolone
antimicrobial agents tend to involve side effects, such as
induction of convulsion in a combined use with a non-steroid
antiinflammatory agent, and phototoxicity. Therefore, development
of safer synthetic quinolone antimicrobial agents has been
sought.
DISCLOSURE OF THE INVENTION
[0005] In the light of these circumstances, the inventors have
conducted extensive investigation for the purpose of providing
excellent compounds fulfilling the above demands. As a result, they
have found that cis-substituted aminocyclopropane derivatives
represented by the following formula (I) and their salts have broad
antimicrobial spectra, exhibiting potent antimicrobial activity
particularly on Gram positive bacteria, especially
quinolone-resistant bacteria including MRSA, and also show
satisfactory in pharmacokinatics and safety.
[0006] The present invention relates to a compound represented by
formula (I) shown below, its salt and their hydrates: 2
[0007] wherein R.sup.1 and R.sup.2 each independently represents a
hydrogen atom or an alkyl group having 1 to 6 carbon atoms which
may be substituted with one or more substituents selected from the
group consisting of a hydroxyl group, a halogen atom, an alkylthio
group having 1 to 6 carbon atoms, and an alkyloxy group having 1 to
6 carbon atoms; n represents an integer of 1 to 3; Q represents a
partial structure having formula: 3
[0008] wherein R.sup.3 represents an alkyl group having 1 to 6
carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a
halogenoalkyl group having 1 to 6 carbon atoms, a substituted or
unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a
substituted or unsubstituted aryl group, a substituted or
unsubstituted heteroaryl group, an alkoxyl group having 1 to 6
carbon atoms, or an alkylamino group having 1 to 6 carbon atoms;
R.sup.4 represents a hydrogen atom or an alkylthio group having 1
to 6 carbon atoms; R.sup.3 and R.sup.4 may be taken together with
part of the mother skeleton to which they are bonded to form a
cyclic structure that may contain a sulfur atom as a ring
constituting atom and/or may be substituted with an alkyl group
having 1 to 6 carbon atoms; R.sup.5 represents a hydrogen atom, an
amino group, a hydroxyl group, a thiol group, a halogenomethyl
group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group
having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon
atoms or an alkoxyl group having 1 to 6 carbon atoms, in which the
amino group may be substituted with one or more substituents
selected from the group consisting of a formyl group, an alkyl
group having 1 to 6 carbon atoms, and an acyl group having 2 to 5
carbon atoms; X.sup.1 represents a halogen atom or a hydrogen atom;
and A represents a nitrogen atom or a partial structure represented
by formula (II): 4
[0009] wherein X.sup.2 represents a hydrogen atom, an amino group,
a halogen atom, a cyano group, a halogenomethyl group, a
halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms,
an alkenyl group having 2 to 6 carbon atoms, an alkynyl group
having 2 to 6 carbon atoms, or an alkoxyl group having 1 to 6
carbon atoms, in which the amino group may be substituted with one
or more substituents selected from the group consisting of a formyl
group, an alkyl group having 1 to 6 carbon atoms and an acyl group
having 2 to 5 carbon atoms; and X.sup.2 and R.sup.3 may be taken
together with part of the mother skeleton to which they are bonded
to form a cyclic structure that may contain an oxygen atom, a
nitrogen atom or a sulfur atom as a ring constituting and/or may be
substituted with an alkyl group having 1 to 6 carbon atoms;
[0010] and Y represents a hydrogen atom, a phenyl group, an
acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl
group, a choline group, a dimethylaminoethyl group, a 5-indanyl
group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl
group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6
carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or
a phenylalkyl group having 1 to 6 carbon atoms in the alkyl moiety
thereof;
[0011] and the two substituents on the cyclopropane ring, 5
[0012] are in a cis-configuration.
[0013] The present invention also relates to:
[0014] a compound of formula (I), wherein Q is a partial structure
represented by formula: 6
[0015] wherein R.sup.3, R.sup.4, R.sup.5, X.sup.1, X.sup.2, and Y
are as defined above, or a salt or hydrate thereof or a hydrate of
the salt;
[0016] a compound of formula (I), wherein Q is a
6-carboxy-9-fluoro-2,3-di-
hydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazin-10-yl
group of formula: 7
[0017] or a salt or hydrate thereof or a hydrate of the salt;
[0018] a compound of formula (I), wherein Q is a
8-amino-6-carboxy-9-fluor-
o-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazin-10-yl
group of formula: 8
[0019] or a salt or hydrate thereof or a hydrate of the salt;
[0020] a compound of formula (I), wherein Q is a
5-amino-3-carboxy-6-fluor-
o-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxyl-4-oxoquinolin--
7-yl group of formula: 9
[0021] or a salt or hydrate thereof or a hydrate of the salt;
[0022] a compound of formula (I), wherein Q is a
5-amino-3-carboxy-6-fluor-
o-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinolin-7--
yl group of formula: 10
[0023] or a salt or hydrate thereof or a hydrate of the salt; a
compound of formula (I), wherein Q is a
3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-c-
yclopropyl]-1,4-dihydro-8-methoxyl-4-oxoquinolin-7-yl group of
formula: 11
[0024] or a salt or hydrate thereof or a hydrate of the salt;
[0025] a compound of formula (I), wherein n is 2, or a salt or
hydrate thereof or a hydrate of the salt;
[0026] a compound of formula (I), wherein R.sup.1 and R.sup.2 are
each a hydrogen atom, or a salt or hydrate thereof or a hydrate of
the salt;
[0027] a compound of formula (I), wherein R.sup.3 is a
halogenocyclopropyl group, or a salt or hydrate thereof or a
hydrate of the salt;
[0028] a compound of formula (I), wherein R.sup.3 is a
1,2-cis-2-halogenocyclopropyl group, or a salt or hydrate thereof
or a hydrate of the salt;
[0029] a compound of formula (I), wherein R.sup.3 is a
stereochemically pure substituent, or a salt or hydrate thereof or
a hydrate of the salt;
[0030] a compound of formula (I), wherein R.sup.3 is a
(1R,2S)-2-halogenocyclopropyl group, or a salt or hydrate thereof
or a hydrate of the salt;
[0031] a compound of formula (I), wherein R.sup.3 is a
(1R,2S)-2-fluorocyclopropyl group, or a salt or hydrate thereof or
a hydrate of the salt;
[0032] a compound of formula (I), wherein X.sup.1 is a halogen
atom, or a salt or hydrate thereof or a hydrate of the salt;
[0033] a compound of formula (I), wherein X.sup.1 is a fluorine
atom, or a salt or hydrate thereof or a hydrate of the salt;
[0034] a compound of formula (I) which is a stereochemically pure
compound, or a salt or hydrate thereof or a hydrate of the
salt;
[0035]
5-amino-7-{3-[(1S,2S)-2-aminocyclopropyl]-1-pyrrolidinyl}-6-fluoro--
1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carb-
oxylic acid or a salt or hydrate thereof or a hydrate of the
salt;
[0036] a drug containing any of the above-described compounds,
hydrates thereof, salts thereof, and hydrates of the salts as an
active ingredient; and
[0037] an antimicrobial agent containing any of the above-described
compounds, hydrates thereof, salts thereof, and hydrates of the
salts as an active ingredient.
[0038] The present invention also relates to a compound represented
by formula (VI) shown below, a salt or hydrate thereof, and a
hydrate of the salt: 12
[0039] wherein R.sup.1 and R.sup.2 each independently represents a
hydrogen atom or an alkyl group having 1 to 6 carbon atoms which
may be substituted with one or more substituents selected from the
group consisting of a hydroxyl group, a halogen atom, an alkylthio
group having 1 to 6 carbon atoms, and an alkyloxy group having 1 to
6 carbon atoms; one of R.sup.1 and R.sup.2 may be a protective
group for amino group; n represents an integer of 1 to 3; Q'
represents a hydrogen atom or a protective group for amino group;
and the two substituents on the cyclopropane ring, 13
[0040] are in a cis-configuration;
[0041] a compound of formula (VI), wherein the protective group for
amino group is selected from the group consisting of a substituted
or unsubstituted alkoxycarbonyl group, a substituted or
unsubstituted aralkyloxycarbonyl group, a substituted or
unsubstituted acyl group, a substituted or unsubstituted alkyl
group, a substituted or unsubstituted aralkyl group, and a
substituted silyl group, or a salt or hydrate thereof or a hydrate
of the salt;
[0042] a compound of formula (VI), wherein the protective group for
amino group is selected from the group consisting of a
t-butoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a
benzyloxycarbonyl group, a p-methoxylbenzyloxycarbonyl group, a
p-nitrobenzyloxycarbonyl group, an acetyl group, a methoxylacetyl
group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl
group, a formyl group, a benzoyl group, a t-butyl group, a benzyl
group, a p-nitrobenzyl group, a p-methoxybenzyl group, a
triphenylmethyl group, a methoxymethyl group, a t-butoxymethyl
group, a tetrahydropyranyl group, a 2,2,2-trichloroethoxymethyl
group, a trimethylsilyl group, an isopropyldimethylsilyl group, a
t-butyldimethylsilyl group, a tribenzylsilyl group, and a
t-butyldiphenylsilyl group, or a salt or hydrate thereof or a
hydrate of the salt;
[0043] a compound of formula (VI), wherein Q' and one of R.sup.1
and R.sup.2 are different protective groups for amino group, or a
salt or hydrate thereof or a hydrate of the salt;
[0044] a compound of formula (VI) which is a stereochemically pure
compound, or a salt or hydrate thereof or a hydrate of the
salt;
[0045] and
1-benzyloxycarbonyl-3-[(1S,2S)-2-t-butoxycarbonylaminocycloprop-
yl]pyrrolidine or a salt or hydrate thereof or a hydrate of the
salt.
[0046] The compound according to the present invention, represented
by formula (I): 14
[0047] namely, formula: 15
[0048] is described with reference to the substituents thereof.
[0049] Substituents R.sup.1 and R.sup.2 each independently
represents a hydrogen atom or an alkyl group having 1 to 6 carbon
atoms which may be substituted with one or more substituents
selected from the group consisting of a hydroxyl group, a halogen
atom, an alkylthio group having 1 to 6 carbon atoms, and an
alkyloxy group having 1 to 6 carbon atoms.
[0050] The alkyl group may be a straight-chain or branched having 1
to 6 carbon atoms and preferably is a methyl group, an ethyl group,
an n-propyl group, and an isopropyl group. The hydroxyl-substituted
alkyl group having 1 to 6 carbon atoms may be a straight-chain or
branched and preferably are a hydroxyethyl group and a
hydroxypropyl group.
[0051] The alkylthio group having 1 to 6 carbon atoms preferably
includes a methylthio group and an ethylthio group. The alkyloxy
group having 1 to 6 carbon atoms preferably are a methoxyll group
and an ethoxyl group.
[0052] Substituent R.sup.3 represents an alkyl group having 1 to 6
carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a
halogenoalkyl group having 1 to 6 carbon atoms, a substituted or
unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a
substituted or unsubstituted aryl group, a substituted or
unsubstituted heteroaryl group, an alkoxyl group having 1 to 6
carbon atoms, or an alkylamino group having 1 to 6 carbon
atoms.
[0053] The alkyl group having 1 to 6 carbon atoms preferably are an
ethyl group. The alkenyl group having 2 to 6 carbon atoms
preferably are a vinyl group or a 1-isopropenyl group. The
halogenoalkyl group having 1 to 6 carbon atoms preferably are a
2-fluoroethyl group. The cycloalkyl group preferably is a
cyclopropyl group. The substituent for the cycloalkyl group
preferably is a halogen atom, particularly a fluorine atom.
[0054] The aryl group which may have a substituent includes a
phenyl group and a phenyl group having 1 to 3 substituents selected
from the group consisting of a halogen atom (e.g., fluorine,
chlorine, and bromine), a lower alkyl group having 1 to 6 carbon
atoms, a hydroxyl group, an amino group, a nitro group, a lower
alkoxyl group having 1 to 6 carbon atoms, etc., and preferably are
a phenyl group, a 2-fluorophenyl group, a 4-fluorophenyl group,
2,4-difluorophenyl group, and a 2-fluoro-4-hydroxyphenyl group.
[0055] The heteroaryl group is a substituent derived from an
aromatic heterocyclic compound containing at least one hetero atom
selected from a nitrogen atom, an oxygen atom and a sulfur atom and
includes a pyridyl group and a pyrimidyl group. The substituents on
the heteroaryl group preferably are an alkyl group and a halogen
atom.
[0056] The alkoxyl group having 1 to 6 carbon atoms preferably are
a methoxyl group. The alkylamino group having 1 to 6 carbon atoms
preferably are a methylamino group.
[0057] Substituent R.sup.3 is preferably a cycloalkyl group or a
halogenocycloalkyl group, still preferably a cyclopropyl group or a
2-halogenocyclopropyl group, in which the halogen atom is
preferably a fluorine atom.
[0058] Substituent R.sup.4 represents a hydrogen atom or an
alkylthio group having 1 to 6 carbon atoms, or R.sup.3 and R.sup.4
may be taken together with part of the mother skeleton (that is, so
as to the nitrogen atom to which R.sup.3 is bonded and the carbon
atom to which R.sup.4 is bonded to are involved) to form a cyclic
structure. The ring formed may contain a sulfur atom as a ring
constituting atom. It may be substituted with an alkyl group having
1 to 6 carbon atoms. The ring can be a 4- to 6-membered ring and
may be saturated, partially saturated or unsaturated. The alkylthio
group having 1 to 6 carbon atoms preferably are a methylthio group
and an ethylthio group.
[0059] The condensed ring structure thus formed includes the
following structures. 16
[0060] X.sup.1 represents a halogen atom or a hydrogen atom.
[0061] As for the halogen atom, a fluorine atom is preferable.
X.sup.1 preferably is a fluorine atom or a hydrogen atom.
[0062] Where A is a partial structure of formula (II): 17
[0063] X.sup.2 represents a hydrogen atom, an amino group, a
halogen atom, a cyano group, a halogenomethyl group, a
halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms,
an alkenyl group having 2 to 6 carbon atoms, an alkynyl group
having 2 to 6 carbon atoms, or an alkoxyl group having 1 to 6
carbon atoms. The amino group may have one or more substituents
selected from the group consisting of a formyl group, an alkyl
group having 1 to 6 carbon atoms and an acyl group having 2 to 5
carbon atoms.
[0064] The alkyl group may be a straight-chain or branched having 1
to 6 carbon atoms and preferably are a methyl group, an ethyl
group, an n-propyl group, and an isopropyl group. The alkenyl group
may be a straight-chain or branched having 2 to 6 carbon atoms and
preferably is a vinyl group. The alkynyl group may be a
straight-chain or branched having 2 to 6 carbon atoms and
preferably is an ethynyl group. The halogenomethyl group may
contain 1 to 3 halogen atoms, and the halogen atom thereof is
preferably a fluorine atom. The alkoxyl group may be those having 1
to 6 carbon atoms and preferably is a methoxyl group. The
halogenomethoxyl group may have 1 to 3 halogen atoms, and the
halogen atom thereof is preferably a fluorine atom.
[0065] R.sup.3 and X.sup.2 may be taken together with part of the
mother skeleton (that is, so as to the nitrogen atom to which
R.sup.3 is bonded and the carbon atom to which X.sup.2 is bonded
are involved) to form a cyclic structure that may contain an oxygen
atom, a nitrogen atom or a sulfur atom as a ring constituting atom
and/or may be substituted with an alkyl group having 1 to 6 carbon
atoms. The cyclic structure can be a 4- to 7-membered ring and may
be saturated, partially saturated or unsaturated.
[0066] The condensed ring structure thus formed includes the
following structures. 18
[0067] A
6-carboxy-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-
benzoxazin-10-yl group is particularly preferred of them.
[0068] Substituent R.sup.5 represents a hydrogen atom, an amino
group, a hydroxyl group, a thiol group, a halogenomethyl group, an
alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2
to 6 carbon atoms, -an alkynyl group having 2 to 6 carbon atoms or
an alkoxyl group having 1 to 6 carbon atoms, in which the amino
group may be substituted with one or more substituents selected
from the group consisting of a formyl group, an alkyl group having
1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon
atoms.
[0069] The alkyl group can be a straight-chain or branched having 1
to 6 carbon atoms and preferably is a methyl group, an ethyl group,
an n-propyl group, and an isopropyl group. The alkenyl group can be
a straight-chain or branched having 2 to 6 carbon atoms and
preferably is a vinyl group. The alkynyl group may be a
straight-chain or branched having 2 to 6 carbon atoms and
preferably is an ethynyl group. The halogenomethyl group may
contain 1 to 3 halogen atoms, and the halogen atom thereof
preferably is a fluorine atom. The alkoxyl group can be those
having 1 to 6 carbon atoms and preferably is a methoxyl group.
[0070] The acyl group having 2 to 5 carbon atoms which may be a
substitutent for the amino group preferably are an acetyl group, a
propanoly group and a butanoyl group.
[0071] Where X.sup.2 or R.sup.5 is an amino group, a hydroxyl group
or a thiol group, these groups may be protected by commonly used
protective groups, such as a substituted or unsubstituted
alkoxycarbonyl group, a substituted or unsubstituted
aralkyloxycarbonyl group, a substituted or unsubstituted acyl
group, a substituted or unsubstituted alkyl group, a substituted or
unsubstituted aralkyl group, and a silyl group substituted with an
alkyl group or an aralkyl group (they may be the same or
different).
[0072] Specific examples of the protective group include
substituted or unsubstituted alkoxycarbonyl groups, e.g., a
t-butoxycarbonyl group and a 2,2,2-trichloroethoxycarbonyl group;
substituted or unsubstituted aralkyloxycarbonyl groups, e.g., a
benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, and a
p-nitrobenzyloxycarbonyl group; substituted or unsubstituted acyl
groups, e.g., an acetyl group, a methoxyacetyl group, a
trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, a
formyl group, and a benzoyl group; substituted or unsubstituted
alkyl or aralkyl groups, e.g., a t-butyl group, a benzyl group, a
p-nitrobenzyl group, a p-methoxybenzyl group, a triphenylmethyl
group, and a phenethyl group; ether groups, e.g, a methoxymethyl
group, a t-butoxymethyl group, a tetrahydropyranyl group, and a
2,2,2-trichloroethoxymethyl group; and substituted silyl groups,
e.g., a trimethylsilyl group, an isopropyldimethylsilyl group, a
t-butyldimethylsilyl group, a tribenzylsilyl group, and a
t-butyldiphenylsilyl group. The compounds whose substituents are
protected by these protective groups are particularly useful as an
intermediate for preparing the compounds of formula (I).
[0073] Y represents a hydrogen atom, a phenyl group, an
acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl
group, a choline group, a dimethylaminoethyl group, a 5-indanyl
group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl
group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6
carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or
a phenylalkyl group having 1 to 6 carbon atoms in the alkyl moiety
thereof.
[0074] The alkyl group having 1 to 6 carbon atoms preferably are a
methyl group, an ethyl group, a propyl group, an isopropyl group, a
butyl group and a t-butyl group. The alkoxymethyl group having 2 to
7 carbon atoms preferably are a methoxymethyl group and an
ethoxymethyl. The phenylalkyl group having 1 to 6 carbon atoms in
the alkyl moiety thereof preferably are a benzyl group and a
phenetyl group.
[0075] Where A is a partial structure represented by formula (II),
a preferable combination of substituents R.sup.5 and X.sup.2 is
that R.sup.5 is selected from an amino group, a hydrogen atom, a
hydroxyl group, and an alkyl group having 1 to 6 carbon atoms, and
X.sup.2 is selected from an alkyl group having 1 to 6 carbon atoms,
an alkoxyl group having 1 to 6 carbon atoms, a halogenomethoxyl
group, and a hydrogen atom. In a still preferred combination,
R.sup.5 is an amino group, a hydrogen atom, a hydroxyl group or a
methyl group, and X.sup.2 is a methyl group, a methoxyl group, a
difluoromethoxyl group or a hydrogen atom.
[0076] In the above case, X.sup.1 preferably is a fluorine atom
with respect to R.sup.5 and X.sup.2. Where X.sup.1 and X.sup.2 are
both a halogen atom, X.sup.1 preferably is a fluorine atom, and
X.sup.2 preferably is a fluorine atom or a chlorine atom.
[0077] The compounds according to the present invention are
characterized in that the quinolone skeleton has a substituent
represented by formula: 19
[0078] at the 7-position or a corresponding position, namely, the
formula that the amino group or alkylamino group: 20
[0079] and a 4-membered (n=1) to 6-membered (n=3)
nitrogen-containing saturated heterocyclic substituent: 21
[0080] are bonded to the cyclopropyl group.
[0081] While the amino moiety and the nitrogen-containing saturated
heterocyclic moiety can be in a cis- or trans-configuration with
respect to the cyclopropyl group (cyclopropane ring), a
cis-configuration shown below is preferred. 22
[0082] Where n is 2 or 3, the nitrogen-containing saturated
heterocyclic moiety and the cyclopropane ring are bonded in two
modes to provide isomers. Such isomers are illustrated below,
taking the structure wherein n=2 for instance. Similar isomers are
produced when n is 3. The present invention is intended to embrace
all these isomers under the scope thereof. 23
[0083] The cyclopropyl moiety may have further substituents, for
example, a fluorine atom, a methyl group, an ethyl group, a
trifluoromethyl group, etc.
[0084] The halogenocyclopropyl group as R.sup.3 is then described.
The substituent halogen atom includes a fluorine atom and a
chlorine atom, with a fluorine atom being preferred.
[0085] It is particularly preferred that the substituent halogen
atom and the pyridonecarboxylic acid moiety be in a
cis-configuration with respect to the cyclopropane ring.
[0086] Regardless of stereoisomerism of the 7-positioned
substituent, the cis-2-halogenocyclopropyl moiety of R.sup.3 makes
a pair of antipodes, each of which was observed to exhibit potent
antimicrobial activity and high safety.
[0087] Where the compound of formula (I) has such a structure that
produces diastereomers, it is desirable to administer a compound
comprising a pure diastereomer in administration to humans or
animals. The language "a compound comprising a pure diastereomer"
as used herein is construed as including not only a compound
containing no other diastereomer at all but a compound containing
other diastereomers to such an extent that the compound is
recognized to be stereochemically pure as a whole. In other words,
it is construed as meaning that other diastereomers may exist to
some extent as long as the existence gives no substantial influence
on physiological activities or physicochemical constants.
[0088] The language "stereochemically pure" as used herein is
intended to mean that a compound comprises only one of its
stereoisomers ascribed to its asymmetric carbon atom. The latitude
of the term "pure" in "pure diastereomer" also applies here.
[0089] The pyridonecarboxylic acid derivative of the present
invention may present in either a free form or a form of an acid
addition salt or a carboxylic acid salt. Acid addition salts
include inorganic acid salts, such as a hydrochloride, a sulfate, a
nitrate, a hydrobromide, a hydroiodide, and a phosphate; and
organic acid salts, such as an acetate, a metanesulfonate, a
benzenesulfonate, a toluenesulfonate, a citrate, a maleate, a
fumarate, and a lactate.
[0090] The carboxylic acid salts include inorganic salts and
organic salts, such as alkali metal salts, e.g., a lithium salt, a
sodium salt, and a potassium salt; alkaline earth metal salts,
e.g., a magnesium salt and a calcium salt; an ammonium salt; a
triethylamine salt, an N-methylglucamine salt, and a
tris-(hydroxymethyl)aminomethane salt.
[0091] The free pyridonecarboxylic acid derivatives, acid addition
salts thereof, and carboxylic acid salts thereof may be present as
a hydrate.
[0092] On the other hand, quinolone derivatives with the carboxylic
acid moiety thereof having an ester form are useful as an
intermediate for synthesis or a pro-drug. For example, alkyl
esters, benzyl esters, alkoxylalkyl esters, phenylalkyl esters, and
phenyl esters are useful as synthetic intermediates.
[0093] Esters which can be used as pro-drugs are those which are
susceptible to an in vivo cleavage to form a free carboxylic acid,
including an acetoxymethyl ester, a pivaloyloxymethyl ester, an
ethoxycarbonyl ester, a choline ester, a dimethylaminoethyl ester,
a 5-indanyl ester, a phthalidinyl ester, a
5-alkyl-2-oxo-1,3-dioxol-4-ylmet- hyl ester, and oxoalkyl esters,
such as a 3-acetoxy-2-oxobutyl ester.
[0094] The compound of formula (I) can be prepared through various
processes. A preferred process comprises reacting a compound
represented by formula (III): 24
[0095] wherein X.sup.3 represents a leaving group, such as a
fluorine atom, a chlorine atom, a bromine atom, an alkylsulfonyl
group having 1 to 3 carbon atoms, or an arylsulfonyl group, e.g., a
benzenesulfonyl group or a toluenesulfonyl group; Y has the same
meaning as in formula (I) or represents a boron-containing group
represented by formula (IV):
--B(R.sup.6)R.sup.7 (IV)
[0096] wherein R.sup.6 and R.sup.7 each represents a fluorine atom
or a lower alkylcarbonyloxy group;
[0097] and R.sup.3, R.sup.4, R.sup.5, X.sup.1, and X.sup.2 are as
defined in formula (I), with a compound represented by formula (V):
25
[0098] wherein R.sup.1, R.sup.2, and n are as defined in formula
(I), except that R.sup.1 may be a nitrogen-protective group Rx.
[0099] Any protective group generally used in the art can be used
as protective group Rx. Examples of useful protective groups
include alkoxylcarbonyl groups, e.g., a t-butoxycarbonyl group and
a 2,2,2-trichloroethoxycarbonyl group;
[0100] aralkyloxycarbonyl groups, e.g., a benzyloxycarbonyl group,
a p-methoxybenzyloxycarbonyl group, and a p-nitrobenzyloxycarbonyl
group; acyl groups, e.g., an acetyl group, a methoxyacetyl group, a
trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, a
formyl group, and a benzoyl group; alkyl or aralkyl groups, e.g., a
t-butyl group, a benzyl group, a p-nitrobenzyl group, a
p-methoxybenzyl group, and a triphenylmethyl group; ether groups,
e.g, a methoxymethyl group, a t-butoxymethyl group, a
tetrahydropyranyl group, and a 2,2,2-trichloroethoxymethyl group;
and substituted silyl groups, e.g., a trimethylsilyl group, an
isopropyldimethylsilyl group, a t-butyldimethylsilyl group, a
tribenzylsilyl group, and a t-butyldiphenylsilyl group, or an acid
addition salt thereof.
[0101] The resulting compound in which Y is an alkyl group having 1
to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms
or a phenylalkyl group having 1 to 6 carbon atoms in the alkyl
moiety thereof can be converted to the corresponding carboxylic
acid by hydrolysis under an acidic or basic condition commonly used
for hydrolysis of carboxylic acid esters. The protective group, if
any, is removed under properly selected conditions to obtain a
desired compound (I).
[0102] The compound obtained by the substitution reaction between
the compound (III) wherein Y is the group (IV) and the compound (V)
can be converted to the corresponding carboxylic acid by treatment
with an acidic or basic compound.
[0103] The substitution reaction between the compound of formula
(III) and the compound of formula (V) is carried out with or
without a solvent. The solvent, if used, is not limited as long as
it is inert under the reaction conditions. Suitable solvents
include dimethyl sulfoxide, pyridine, acetonitrile, ethanol,
chloroform, dimethylformamide, dimethylacetamide,
N-methylpyrrolidone, tetrahydrofuran, water, and 3-methoxybutanol.
These solvents may be used as a mixture thereof.
[0104] The reaction is usually performed at room temperature to
200.degree. C., preferably 25 to 150.degree. C., for 0.5 to 48
hours. The reaction usually completes in about 0.5 to 2 hours. It
is advantageous to conduct the reaction in the presence of an acid
acceptor, such as an inorganic base (e.g., an alkali metal or
alkaline earth metal carbonate or hydrogencarbonate) or an organic
base (e.g., triethylamine, pyridine or
1,8-diazabicycloundecene).
[0105] The compound of formula (V) can be prepared by various
processes. A preferred process is shown in Reference Examples
hereinafter given, but the process is not limited thereto. Most
generally, the compound of formula (V) is prepared by removing the
protective group from a compound represented by formula (VI) shown
below, in which the nitrogen atom is protected by a protective
group Q'. 26
[0106] wherein R.sup.1 and R.sup.2 each represent a hydrogen atom
or an alkyl group having 1 to 6 carbon atoms, which may have one or
more substituents selected from the group consisting of a hydroxyl
group, a halogen atom, an alkylthio group having 1 to 6 carbon
atoms, and an alkyloxy group having 1 to 6 carbon atoms; one of
R.sup.1 and R.sup.2 may be an protective group for amino group; n
represents an integer of 1 to 3; Q' represents a protective group
for amino group; and the two substituents on the cyclopropane ring,
27
[0107] are in a cis-configuration.
[0108] The compound (VI) may exist in the form of a salt, a
hydrate, or a hydrate of the salt. Acid addition salts include
inorganic acid salts and organic acid salts. Examples of the
inorganic acid salts are a hydrochloride, a sulfate, a nitrate, a
hydrobromide, a hydroiodide, and a phosphate. Examples of the
organic acid salts include sulfonates, such as a metanesulfonate, a
benzenesulfonate, and a toluenesulfonate, and carboxylates, such as
an acetate, a citrate, a maleate, a fumarate, and a lactate.
[0109] Where Q' and one of R.sup.1 and R.sup.2 both represent an
protective group for amino group, while they may be the same or
different, it is advantageous for the preparation of the compound
(I) that these protective groups are different so that they are
cleaved under the respective different reaction conditions.
[0110] The protective group for amino group as R.sup.1 or R.sup.2
and Q' includes substituted or unsubstituted alkoxycarbonyl groups,
e.g., a t-butoxycarbonyl group and a 2,2,2-trichloroethoxycarbonyl
group; substituted or unsubstituted aralkyloxycarbonyl groups,
e.g., a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl
group, and a p-nitrobenzyloxycarbonyl group; substituted or
unsubstituted acyl groups, e.g., an acetyl group, a methoxyacetyl
group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl
group, a formyl group, and a benzoyl group; substituted or
unsubstituted alkyl or aralkyl groups, e.g., a t-butyl group, a
benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, and a
triphenylmethyl group; ether groups, e.g, a methoxymethyl group, a
t-butoxymethyl group, a tetrahydropyranyl group, and a
2,2,2-trichloroethoxymethyl group; and substituted silyl groups,
e.g., a trimethylsilyl group, an isopropyldimethylsilyl group, a
t-butyldimethylsilyl group, a tribenzylsilyl group, and a
t-butyldiphenylsilyl group.
[0111] Cis-2-fluorocyclopropylamine comprising a pure isomer, which
is preferred for the synthesis of the compound of formula (I)
comprising a pure isomer, can be synthesized by, for example, the
process described in JP-A-2-231475 (the term "JP-A" as used herein
means an "unexamined published Japanese patent application").
Synthesis of the compound of formula (I) comprising a pure isomer
from the resulting optically active cis-2-fluorocyclopropylamine
derivative can be carried out by, for example, the process
described in JP-A-2-231475.
[0112] The compounds of the present invention have potent
antimicrobial activity and are therefore useful as drugs for
humans, animals or fishes, agricultural chemicals, or food
preservatives.
[0113] For use as drugs for humans, the dose of the compound is in
the range of from 50 mg to 1 g, and preferably from 100 mg to 300
mg, per day for an adult.
[0114] For veterinary use, the dose is generally in the range of
from 1 to 200 mg, and preferably from 5 to 100 mg, per kg of body
weight per day while varying depending on the purpose of
administration (for therapy or for prevention), the kind and the
size of the animal, the kind of the pathogenic organisms, and
severity of symptom.
[0115] The above-mentioned daily dose is given once a day or in 2
to 4 divided doses. If necessary, a daily dose may exceed the
above-specified range.
[0116] The compounds according to the present invention are active
on a broad range of microorganisms causing various infectious
diseases and effective to prevent, alleviate or cure diseases
caused by these pathogens.
[0117] Examples of bacteria or bacterium-like microorganisms on
which the compounds of the invention are effective include
staphylococci, Streptococcus pyogenes, Streptococcus haemolyticus,
Streptococcus faecalis, Streptococcus pneumoniae,
peptostreptococci, Neisseria gonorrhoeae, Escherichia coli,
Citrobacter sp., Shigella sp., Klebsiella pneumoniae, Enterobacter
sp., Serratia sp., Proteus sp., Pseudomonas aeruginosa, Haemophilus
influenzae, Acinetobacter sp., Campylobacter sp., and Chlamydozoon
trachomatis.
[0118] Diseases which are caused by these pathogens include
folliculitis, furuncle, carbuncle, erysipelas, phlegmon,
lymphangitis/lymphadenitis, felon, subcutaneous abscess,
spiradenitis, acne agminata, infectious atheroma, perianal abscess,
mastadenitis, superficial secondary infections after trauma, burn
or surgery trauma, pharyngolaryngitis, acute bronchitis,
tonsillitis, chronic bronchitis, bronchiectasis, diffuse
panbronchiolitis, secondary infections of chronic respiratory
diseases, pneumonia, pyelonephritis, cystitis, prostatitis,
epididymitis, gonococcal urethritis, non-gonococcal urethritis,
cholecystitis, cholangitis, bacillary dysentery, enteritis,
adnexitis, intrauterine infections, bartholinitis, blepharitis,
hordeolum, dacryocystitis, tarsadenitis, keratohelcosis, otitis
media, sinusitis, paradentosis, pericoronitis, gnathitis,
peritonitis, endocarditis, septicemia, meningitis, and skin
infections.
[0119] The compounds of the present invention are also effective on
various microorganisms causing veterinary diseases, such as those
belonging to the genera Escherichia, Salmonella, Pasteurella,
Haemophilus, Bordetella, Staphylococcus, and Mycoplasma.
Illustrative examples of the veterinary diseases include those of
fowl, such as colibacillosis, pullorum disease, avian paratyphosis,
fowl cholera, infectious coryza, staphylomycosis, and
mycoplasmosis; those of pigs, such as colibacillosis,
salmonellosis, pasteurellosis, hemophilus infections, atrophic
rhinitis, exudative epidermitis, and mycoplasmosis; those of
cattle, such as colibacillosis, salmonellosis, hemorrhagic
septicemia, mycoplasmosis, bovine contagious pleuropneumonia, and
bovine mastitis; those of dogs, such as colisepsis, salmonellosis,
hemorrhagic septicemia, pyometra, and cystitis; those of cats, such
as exudative pleurisy, cystitis, chronic rhinitis, and hemophilus
infections; and those of kittens, such as bacterial diarrhea and
mycoplasmosis.
[0120] Dosage forms of pharmaceutical preparations containing the
compound of the present invention are appropriately selected
according to the administration route and can be prepared by
conventional preparation methods. Examples of dosage forms for oral
administration include tablets, powders, granules, capsules,
solutions, syrups, elixirs, and oily or aqueous suspensions.
[0121] Injectable preparations may contain adjuvants, such as
stabilizers, antiseptics, and solubilizers. The injectable solution
which may contain these adjuvants may be put into a container and
solidified by, for example, lyophilization to prepare a solid
preparation which is dissolved on use. The container may contain
either a single dose or multiple doses.
[0122] Preparations for external application include solutions,
suspensions, emulsions, ointments, gels, creams, lotions, and
sprays.
[0123] Solid preparations may contain, in addition to the active
compound, pharmaceutically acceptable additives. For example, the
active compound is mixed with additives selected according to
necessity from among fillers, extenders, binders, disintegrators,
absorption accelerators, wetting agents, and lubricants and
formulated into solid preparations.
[0124] Liquid preparations include solutions, suspensions, and
emulsions. They may contain adjuvants, such as suspending agents,
emulsifiers, and so forth.
[0125] The compound can be administered to animals orally either
directly or by mixing with feedstuff, or in a dissolved form
directly given to animals or by mixing with water or feedstuff or
non-orally by injection.
[0126] For veterinary use, the compound can be formulated into
powders, fine granules, soluble powders, syrups, solutions, and
injections according to the customary methods in the art.
[0127] Formulation Examples are shown below.
Formulation Example 1
[0128]
1 Formulation Example 1 Capsules Compound of Example 2 100.0 mg
Corn starch 23.0 mg CMC.cndot.Ca 22.5 mg Hydroxymethyl cellulose
3.0 mg Magnesium stearate 1.5 mg Total: 150.0 mg Formulation
Example 2 Solution Compound of Example 2 1 to 10 g Acetic acid or
sodium hydroxide 0.5 to 2 g Ethyl p-hydroxybenzoate 0.1 g Purified
water 87.9 to 98.4 g Total: 100 g Formulation Example 3 Powder for
Mixing with Feed Compound of Example 2 1 to 10 g Corn starch 89.5
to 98.5 g Light anhydrous silicic acid 0.5 g Total: 100 g
[0129] Best Mode of Carrying Out the Invention
[0130] The present invention will further be illustrated in greater
detail by way of Examples and Reference Examples, but the present
invention should not be construed as being limited thereto. The
antimicrobial activity of the compounds prepared was examined in
accordance with the standard method specified by the Japan
Chemotherapeutic Society, and the results obtained were expressed
in terms of minimum inhibitory concentration (MIC; .mu.g/ml).
EXAMPLE 1
5-Amino-7-[3-(1,2-cis-2-aminocyclopropyl)-1-pyrrolidinyl]-6-fluoro-1-[(1R,-
2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic
Acid (Isomer A)
[0131] Triethylamine (2.5 ml) was added to a solution of 316.1 mg
(1.01 mmol) of
5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,-
4-dihydro-4-oxoquinoline-3-carboxylic acid and 343.6 mg (1.52 mmol)
of
1-benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylaminocyclopropyl)-pyrrolidin-
e (isomer A) in 5 ml of dimethyl sulfoxide, and the mixture was
heated under reflux at 130.degree. C. for 4 days. The solvent was
removed by evaporation under reduced pressure, and chloroform was
added to the residue, followed by washing successively with a 10%
citric acid aqueous solution and a saturated sodium chloride
aqueous solution. The organic layer was dried over anhydrous sodium
sulfate, and the solvent was evaporated under reduced pressure. To
the residue was added 10 ml of concentrated hydrochloric acid under
cooling with ice. After stirring at room temperature for 30
minutes, water was added to the reaction mixture, followed by
extraction with dichloromethane. The aqueous layer was neutralized
with 5N and 1N sodium hydroxide aqueous solutions and extracted
with chloroform. The organic layer was dried over anhydrous sodium
sulfate, and the solvent was evaporated under reduced pressure. The
residue was recrystallized from ethanol and diethyl ether to give
122.8 mg (29.0%) of the title compound (isomer A) as yellow
crystals.
[0132] .sup.1H-NMR (0.1N-NaOD) .delta. ppm:
[0133] 0.00-0.10 (1H, m), 0.55-0.75 (2H, m), 1.00-1.15 (1H, m),
1.35-1.50 (1H, m), 1.55-1.80 (1H, m), 1.85-2.00 (1H, m), 2.00-2.15
(1H, m), 2.15-2.30 (4H, m), 3.10-3.70 (4H, m), 3.80-3.90 (1H, m),
4.60-5.00 (1H, m), and 8.18 and 8.20 (1H, d each, J=2.9, 2.4 Hz
each).
[0134] Elementary Analysis for
C.sub.21H.sub.24F.sub.2N.sub.4O.sub.3:
[0135] Calcd. (%): C, 60.28; H, 5.78; N, 13.39
[0136] Found (%): C, 60.09; H, 5.96; N, 13.06
EXAMPLE 2
5-Amino-7-[3-(1,2-cis-2-aminocyclopropyl)-1-pyrrolidinyl]-6-fluoro-1-[(1R,-
2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic
Acid (Isomer B)
[0137] Triethylamine (2 ml) was added to a solution of 195.9 mg
(0.63 mmol) of
5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,-
4-dihydro-4-oxoquinoline-3-carboxylic acid and 213.0 mg (0.94 mmol)
of
1-benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylaminocyclopropyl)pyrrolidine
(isomer B) in 4 ml of dimethyl sulfoxide, and the mixture was
heated under reflux at 130.degree. C. for 45 hours. The solvent was
removed by evaporation under reduced pressure, and chloroform was
added to the residue, followed by washing successively with a 10%
citric acid aqueous solution and a saturated sodium chloride
aqueous solution. The organic layer was dried over anhydrous sodium
sulfate, and the solvent was evaporated under reduced pressure. To
the residue was added 10 ml of concentrated hydrochloric acid under
cooling with ice. After stirring at room temperature for 30
minutes, water was added to the reaction mixture, followed by
extraction with dichloromethane. The aqueous layer was neutralized
with 5N and 1N sodium hydroxide aqueous solutions and extracted
with chloroform. The aqueous layer was adjusted to a pH of 10 or
higher with a 5N sodium hydroxide aqueous solution and extracted
with chloroform. The aqueous layer was neutralized with
concentrated hydrochloric acid and 1N hydrochloric acid and
extracted with chloroform. The organic layer was dried over
anhydrous sodium sulfate, and the solvent was evaporated under
reduced pressure. The residue was recrystallized from ethanol and
diethyl ether to give 65.9 mg (25.1%) of the title compound (isomer
B) as yellow crystals.
[0138] .sup.1H-NMR (0.1N-NaOD) .delta. ppm:
[0139] 0.00-0.10 (1H, m), 0.55-0.70 (2H, m), 0.95-1.15 (1H, m),
1.30-1.50 (1H, m), 1.60-1.80 (1H, m), 1.80-2.10 (2H, m), 2.10-2.25
(4H, m), 3.00-3.70 (4H, m), 3.75-3.85 (1H, m), 4.65-4.95 (1H, m),
and 8.13 and 8.14 (1H, d each, J=2.9, 2.0 Hz each).
[0140] Elementary Analysis for
C.sub.21H.sub.24F.sub.2N.sub.4O.sub.3.0.5H.- sub.2O:
[0141] Calcd. (%): C, 59.01; H, 5.90; N, 13.11
[0142] Found (%): C, 59.10; H, 5.66; N, 13.06
EXAMPLE 3
5-Amino-7-{3-[(1S,2S)-2-aminocyclopropyl]-1-pyrrolidinyl}-6-fluoro-1-[(1R,-
2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic
Acid (Isomer B.sup.1)
[0143] Triethylamine (4 ml) was added to a solution of 526.3 mg
(1.69 mmol) of
5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,-
4-dihydro-4-oxoquinoline-3-carboxylic acid and 572.2 mg (2.53 mmol)
of
1-benzyloxycarbonyl-3-[(1S,2S)-2-t--butoxycarbonylaminocyclopropyl]pyrrol-
idine (isomer B) in 8 ml of dimethyl sulfoxide, and the mixture was
heated under reflux at 130.degree. C. for 90 hours. The solvent was
removed by evaporation under reduced pressure, and chloroform was
added to the residue, followed by washing with a 10% citric acid
aqueous solution and a saturated sodium chloride aqueous solution.
The organic layer was dried over anhydrous sodium sulfate, and the
solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography
(chloroform:methanol=9:1) to obtain 551.4 mg of a protected
compound and 141.4 mg of a mixture of the protected compound and
by-products as a brown caramel-like substance.
[0144] To the resulting protected compound (551.4 mg) was added 10
ml of concentrated hydrochloric acid under ice-cooling, followed by
stirring at room temperature for 20 minutes. Water was added to the
reaction mixture, and the mixture was extracted with
dichloromethane. The aqueous layer was neutralized with 5N and 1N
sodium hydroxide aqueous solutions and extracted with chloroform.
The organic layer was removed by evaporation, and the residue was
adjusted to a pH of 10 or higher with water and a 1N sodium
hydroxide aqueous solution and extracted with chloroform. The
aqueous layer was neutralized with concentrated hydrochloric acid
and 1N hydrochloric acid and extracted with chloroform. The first
aqueous layer was adjusted to a pH of 10 or higher with a 5N sodium
hydroxide aqueous solution and extracted with chloroform. The
aqueous layer was neutralized with concentrated hydrochloric acid
and 1N hydrochloric acid and extracted with chloroform. The
combined organic layer was dried over anhydrous sodium sulfate, and
the solvent was evaporated under reduced pressure to obtain 286.1
mg of a crude carboxylic acid.
[0145] The mixture (141.4 mg) of the protected compound and
by-products was similarly treated to obtain 62.3 mg of a crude
carboxylic acid.
[0146] Recrystallization of the resulting crude carboxylic acid
from ethanol gave 204.4 mg (29.0%) of the title compound as yellow
crystals.
[0147] .sup.1H-NMR (0.1N-NaOD) .delta. ppm:
[0148] -0.05-0.05 (1H, m), 0.55-0.65 (2H, m), 0.90-1.10 (1H, m),
1.30-1.40 (1H, m), 1.60-1.70 (1H, m), 1.80-1.90 (1H, m), 2.00-2.10
(1H, m), 2.10-2.20 (4H, m), 3.20-3.30 (1H, m), 3.30-3.40 (2H, m),
3.50-3.60 (1H, m), 3.70-3.80 (1H, m), 4.70-4.95 (1H, m), and 8.11
(1H, brs).
[0149] Elementary Analysis for
C.sub.21H.sub.24F.sub.2N.sub.4O.sub.3:
[0150] Calcd. (%): C, 60.28; H, 5.78; N, 13.39
[0151] Found (%): C, 60.21; H, 5.72; N, 13.15
[0152] Melting Point: 193-196.degree. C.
Reference Example A
Cis-2-methoxycarbonylcyclopropanecarboxylic Acid
[0153] To 150 ml of a methanol solution of 14.68 g (92.8 mmol) of
dimethyl cis-1,2-cyclopropanedicarboxylate was added 67 ml of an
aqueous solution of 7.52 g (113.9 mmol) of potassium hydroxide
under cooling with ice, and the mixture was stirred at room
temperature for 24 hours. After completion of the reaction, the
solvent was removed by evaporation under reduced pressure, and to
the residue was added water. The reaction mixture was washed with
diethyl ether. The aqueous layer was adjusted to pH 2 with
concentrated hydrochloric acid and extracted with ethyl acetate.
The organic layer was dried over anhydrous sodium sulfate, and the
solvent was evaporated under reduced pressure to give 12.38 g
(92.5%) of the title compound as a colorless oily substance.
[0154] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0155] 1.35 (1H, dt, J=8.3, 4.9 Hz), 1.70 (1H, dt, J=6.8, 4.9 Hz),
2.05-2.20 (2H, m), and 3.72 (3H, m).
Reference Example B
t-Butyl Cis-2-methoxycarbonylcyclopropanecarboxylate
[0156] To 70 ml of an anhydrous tetrahydrofuran solution of 6.83 g
(47.4 mmol) of cis-2-methoxycarbonylcyclopropanecarboxylic acid
were added 1.16 g (9.48 mmol) of dimethylaminopyridine and 13.45 g
(61.6 mmol) of di-t-butyl dicarbonate at room temperature, and the
mixture was stirred at the same temperature for 4 hours. After
completion of the reaction, the solvent was removed by evaporation
under reduced pressure, and ethyl acetate was added to the residue.
The mixture was washed successively with 0.5N hydrochloric acid,
water, and a saturated sodium chloride aqueous solution. The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was evaporated under reduced pressure to give 9.49 g
(quantitative) of the title compound as a brown oily substance.
[0157] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0158] 1.10-1.20 (1H, m), 1.44 (9H, s), 1.55-1.65 (1H, m),
1.95-2.05 (2H, m), and 3.67 (3H, s).
Reference Example C
Cis-2-t-butoxycarbonylcyclopropanecarboxylic Acid
[0159] To 100 ml of a methanol solution of 9.49 g (47.4 mmol) of
t-butyl cis-2-methoxycarbonylcyclopropanecarboxylate was added 40
ml of an aqueous solution of 4.06 g (61.5 mmol) of potassium
hydroxide under cooling with ice, followed by stirring at room
temperature for 24 hours. After completion of the reaction, the
solvent was evaporated under reduced pressure. Water was added to
the residue, and the mixture was washed with diethyl ether. The
aqueous layer was adjusted to a pH of 2 to 3 with concentrated
hydrochloric acid and extracted with ethyl acetate. The organic
layer was dried over anhydrous sodium sulfate, and the solvent was
evaporated under reduced pressure to give 7.56 g (85.7%) of the
title compound as a pale yellow solid.
[0160] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0161] 1.30-1.40 (1H, m), 1.45 (9H, s), 1.60-1.65 (1H, m), and
2.00-2.10 (2H, m)
Reference Example D
Ethyl 3-(Cis-2-t-butoxycarbonylcyclopropyl)-3-oxopropionate
[0162] To 100 ml of an anhydrous tetrahydrofuran solution of 7.56 g
(40.6 mmol) of cis-2-t-butoxycarbonylcyclopropanecarboxylic acid
was added 7.57 g (46.7 mmol) of 1,1-carbonyldiimidazole under
cooling with ice. After stirring the mixture was stirred at room
temperature for 2 hours, the solvent was evaporated under reduced
pressure. To 50 ml of an anhydrous tetrahydrofuran solution of the
resulting residue was added 80 ml of an anhydrous tetrahydrofuran
solution of 101.5 mmol of previously prepared magnesium monoethyl
malonate was added, followed by stirring overnight. After
completion of the reaction, the solvent was removed by evaporation
under reduced pressure, and ethyl acetate was added to the residue.
The mixture was washed successively with 0.5N hydrochloric acid, a
saturated sodium hydrogencarbonate aqueous solution, and a
saturated sodium chloride aqueous solution. The organic layer was
dried over anhydrous sodium sulfate, and the solvent was evaporated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane:ethyl acetate=7:3) to give 6.67 g
(64.1%) of the titled compound as a yellow oily substance.
[0163] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0164] 1.20 (1H, dt, J=7.8, 4.9 Hz), 1.29 (3H, t, J=7.3 Hz), 1.42
(9H, s), 1.71 (1H, dt, J=6.8, 4.9 Hz), 2.00-2.10 (1H, m), 2.30-2.40
(1H, m), 3.55 (1H, d, J=15.6 Hz), 3.57 (1H, d, J=15.6 Hz), 4.20
(2H, q, J=7.3 Hz).
Reference Example E
Ethyl 3-(Cis-2-t-butoxycarbonylcyclopropyl)acrylate
[0165] To 70 ml of a methanol solution of 6.67 g (26.0 mmol) of
ethyl 3-(cis-2-t-butoxycarbonylcyclopropyl)-3-oxopropionate was
added 492.2 mg (13.0 mmol) of sodium borohydride at -10.degree. C.,
and the mixture was stirred at that temperature for 20 minutes. A
saturated ammonium chloride aqueous solution was added thereto, and
the reaction mixture was extracted with chloroform. The organic
layer was dried over anhydrous sodium sulfate, and the solvent was
evaporated under reduced pressure to obtain 6.52 g (97.0%) of a
crude alcohol as a colorless oily substance.
[0166] To 150 ml of a dichloromethane solution of the crude alcohol
(6.52 g, 25.2 mmol) were added 7.04 ml (50.4 mmol) of triethylamine
and 2.54 ml (32.8 mmol) of methanesulfonyl chloride while cooling
with ice. After the mixture was stirred at the same temperature for
1.5 hours, 8.30 ml (55.4 mmol) of
1,8-diazabicyclo[5.4.0]-7-undecene was added thereto, followed by
stirring at room temperature for 18 hours. The solvent was
evaporated under reduced pressure, and chloroform was added to the
residue. The mixture was washed successively with 0.1N hydrochloric
acid and a saturated sodium chloride aqueous solution. The organic
layer was dried over anhydrous sodium sulfate, and the solvent was
removed by evaporation under reduced pressure to give 6.07 g
(quantitative) of the title compound as a yellow oily
substance.
[0167] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0168] 1.27 (3H, t, J=7.3 Hz), 1.25-1.35 (1H, m), 1.35-1.45 (1H,
m), 1.46 (9H, s), 1.90-2.05 (2H, m), 4.10-4.20 (2H, m), 6.00 (1H,
d, J=15.6 Hz), and 6.90 (1H, ddd, J=15.6, 8.8, 1.5 Hz).
Reference Example F
Ethyl
3-(Cis-2-t-butoxycarbonylcyclopropyl)-3-nitroethylpropionate
[0169] To 60 ml of a nitromethane solution of 6.07 g (25.2 mmol) of
ethyl 3-(cis-2-t-butoxycarbonylcyclopropyl)-acrylate was added 3.48
ml (27.7 mmol) of tetramethylguanidine at room temperature, and the
mixture was stirred for 6 hours. To the reaction mixture was
further added 0.32 ml (2.52 mmol) of tetramethylguanidine, followed
by stirring for 18 hours. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=85:15) to give 6.536 g (85.9%)
of the title compound as a pale yellow oily substance.
[0170] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0171] 0.95-1.10 (2H, m), 1.20-1.30 (4H, m), 1.46 and 1.48 (9H, s
each), 1.65-1.80 (1H, m), 2.40-2.70 (2H, m), 2.70-2.80 (1H, m),
4.10-4.20 (2H, m), and 4.45-4.55 and 4.60-4.75 (2H, m each)
Reference Example G
3-(Cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one
[0172] To 200 ml of a methanol solution of 6.536 g (21.7 mmol) of
ethyl 3-(cis-2-t-butoxycarbonylcyclopropyl)-3-nitroethylpropionate
were added 5 g of 10% palladium-on-carbon and 13.68 g (217 mmol) of
ammonium formate at room temperature, and the mixture was stirred
at the same temperature for 1.5 hours. After completion of the
reaction, the solvent was evaporated under reduced pressure. Water
was added to the residue, and the mixture was extracted with
chloroform. The organic layer was dried over anhydrous sodium
sulfate, and the solvent was evaporated under reduced pressure to
give a crude amine.
[0173] A toluene solution (150 ml) of the resulting crude amine was
heated at 110 to 120.degree. C. for 2 hours. The solvent was
evaporated under reduced pressure to give 4.89 g (quantitative) of
the title compound as yellow crystals.
[0174] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0175] 0.90-1.10 (2H, m), 1.20-1.35 (1H, m), 1.45 (9H, s),
1.65-1.75 (1H, m), 2.10-2.70 (3H, m), 3.10-3.20 and 3.20-3.30 (1H,
m each), 3.35-3.45 and 3.55-3.65 (1H, m each), and 6.06 (1H,
brs).
Reference Example H
1-Benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one
[0176] To 30 ml of a dimethylformamide solution of 2.288 g (10.2
mmol) of 3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one was
added 406.2 mg (10.2 mmol) of sodium hydride under cooling with
ice, followed by stirring at room temperature for 1.5 hours. Then,
1.81 ml (15.3 mmol) of benzyl chloride was added thereto dropwise,
followed by stirring for 2.5 hours. After completion of the
reaction, water was added to the reaction mixture, and the mixture
was extracted with ethyl acetate, and the organic layer was washed
with water and a saturated sodium chloride aqueous solution. The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was removed by evaporation under reduced pressure. The
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=7:3) to give 1.121 g (35.0%) of
1-benzyl-3-(2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one (isomer
A: an isomer attributed to the steric configuration of the
cyclopropyl group bonded to the carbon atom of the pyrrolidine
ring) as a colorless solid. The column was then eluted with
hexane:ethyl acetate=1:1 to give 670.9 mg (20.9%) of
1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one
(isomer B: an isomer attributed to the steric configuration of the
cyclopropyl group bonded to the carbon atom of the pyrrolidine
ring) as a colorless solid.
[0177] Isomer A:
[0178] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0179] 0.85-1.00 (2H, m), 1.10-1.25 (1H, m), 1.45 (9H, s),
1.65-1.75 (1H, m), 2.25 (1H, dd, J=16.1, 6.4 Hz), 2.35-2.45 (1H,
m), 2.50 (1H, dd, J=16.1, 8.8 Hz), 3.08 (1H, dd, J=9.8, 5.9 Hz),
3.43 (1H, t, J=8.8 Hz), 4.45 (1H, d, J=14.7 Hz), 4.46 (1H, d,
J=14.7 Hz), and 7.20-7.40 (5H, m).
[0180] Isomer B:
[0181] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0182] 0.90-1.00 (1H, m), 1.00-1.10 (1H, m), 1.15-1.25 (1H, m),
1.37 (9H, s), 1.55-1.65 (1H, m), 2.33 (1H, dd, J=16.1, 7.3 Hz),
2.35-2.45 (1H, m), 2.68 (1H, dd, J=16.1, 8.3 Hz), 2.99 (1H, dd,
J=9.3, 5.9 Hz), 3.20 (1H, dd, J=9.3, 7.8 Hz), 4.39 (1H, d, J=14.7
Hz), 4.48 (1H, d, J=14.7 Hz), and 7.20-7.40 (5H, m).
Reference Example I
1-Benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine-2-thione
(Isomer A)
[0183] To 40 ml of a toluene solution of 1.990 g (6.31 mmol) of
1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one
(isomer A) was added 1.378 g (3.41 mmol) of a Lawson's reagent, and
the mixture was stirred at 50 to 60.degree. C. for 1.5 hours. After
completion of the reaction, the reaction mixture was subjected to
silica gel column chromatography (hexane:ethyl acetate=7:3) to give
1.707 g (81.6%) of the title compound (isomer A) as a pale yellow
solid.
[0184] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0185] 0.80-0.90 (1H, m), 0.90-1.00 (1H, m), 1.10-1.20 (1H, m),
1.45 (9H, s), 1.65-1.75 (1H, m), 2.40-2.55 (1H, m), 2.90 (1H, dd,
J=17.6, 5.4 Hz), 3.12 (1H, dd, J=17.6, 8.3 Hz), 3.41 (1H, dd,
J=11.2, 5.4 Hz), 3.75 (1H, dd, J=11.2, 7.8 Hz), 4.97 (1H, d, J=14.2
Hz), 5.01 (1H, d, J=14.2 Hz), 7.30-7.40 (5H, m)
Reference Example J
1-Benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine (Isomer
A)
[0186] To 50 ml of an ethanol solution of 1.70 g (5.13 mmol) of
1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine-2-thione
(isomer A) was added 14 ml of Raney nickel, followed by stirring at
room temperature for 1.5 hours. Any insoluble matter was removed by
filtration, and the solvent was evaporated under reduced pressure.
Chloroform was added to the residue, and the mixture was washed
with 10% aqueous ammonia. The organic layer was dried over
anhydrous sodium sulfate, and the solvent was evaporated under
reduced pressure to give 1.479 g (95.7%) of the title compound
(isomer A) as a pale yellow oily substance.
[0187] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0188] 0.85-0.95 (2H, m), 1.20-1.30 (1H, m), 1.44 (9H, s),
1.50-1.65 (2H, m), 1.85-1.95 (1H, m), 2.10-2.25 (1H, m), 2.40 (1H,
dd, J=8.8, 5.9 Hz), 2.51 (1H, q, J=7.8 Hz), 2.62 (1H, dt, J=8.8,
5.4 Hz), 2.72 (1H, t, J=8.7 Hz), 3.59 (1H, d, J=12.7 Hz), 3.62 (1H,
d, J=12.7 Hz), and 7.20-7.40 (5H, m).
Reference Example K
1-Benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine
(Isomer A)
[0189] To 30 ml of a dichloromethane solution of 1.466 g (4.86
mmol) of 1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)-pyrrolidine
(isomer A) was added 1.39 ml (9.72 mmol) of benzyl chloroformate at
room temperature, and the mixture was stirred at the same
temperature for 15.5 hours, followed by heat-refluxing for 1 hour.
To the reaction mixture was further added 0.70 ml (4.86 mmol) of
benzyl chloroformate, followed by heat-refluxing for 1.5 hours. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=7:3) to give 1.261 g (75.1%) of the title compound as a
colorless oily substance.
[0190] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0191] 0.90-1.00 (2H, m), 1.05-1.15 (1H, m), 1.46 (9H, s),
1.60-1.70 (2H, m), 1.80-1.95 (1H, m), 2.20-2.30 (1H, m), 3.15-3.30
(1H, m), 3.30-3.40 (1H, m), 3.50-3.70 (2H, m), 5.14 (2H, s), and
7.25-7.40 (5H, m).
Reference Example L
1-Benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylaminocyclopropyl)pyrrolidine
(Isomer A)
[0192] To 10 ml of a dichloromethane solution of 1.252 g (3.62
mmol) of
1-benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine
was added 5 ml of trifluoroacetic acid under cooling with ice, and
the mixture was stirred at room temperature for 2 hours. After
completion of the reaction, the solvent was removed by evaporation
under reduced pressure. Toluene was added to the residue, followed
by evaporation to obtain a crude carboxylic acid.
[0193] To 30 ml of a 2-methyl-2-propanol solution of the resulting
crude carboxylic acid were added 0.781 ml (3.62 mmol) of
diphenylphosphoric acid azide and 0.758 ml (5.43 mmol) of
triethylamine, and the mixture was stirred at room temperature for
1 hour and then heated under reflux for 31 hours. After completion
of the reaction, the solvent was evaporated under reduced pressure,
and ethyl acetate was added to the residue. The mixture was washed
successively with a 5% citric acid aqueous solution, a saturated
sodium carbonate aqueous solution, and a saturated sodium chloride
aqueous solution. The organic layer was dried over anhydrous sodium
sulfate, and the solvent was evaporated under reduced pressure. The
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=7:3) to give 6.67 g (64.1%) of ethyl
3-(cis-2-t-butoxycarbonylcyclopropyl)-3-oxopropionate as a yellow
oily substance and 575.2 mg (44.0%) of
1-benzyloxycarbonyl-3-(cis-2-t-butoxyca-
rbonylaminocyclopropyl)pyrrolidine (isomer A) as a colorless oily
substance.
[0194] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0195] 0.20-0.30 (1H, m), 0.75-0.95 (2H, m), 1.44 (9H, s),
1.70-1.90 (2H, m), 2.00-2.10 (1H, m), 2.65-2.75 (1H, m), 3.15-3.30
(1H, m), 3.30-3.40 (1H, m), 3.50-3.65 (2H, m), 4.50-4.65 (1H, brs),
5.13 (2H, s), and 7.30-7.40 (5H, m).
Reference Example M
3-(Cis-2-t-butoxycarbonylaminocyclopropyl)pyrrolidine (Isomer
A)
[0196] To 15 ml of an ethanol solution of 547.3 mg (1.52 mmol) of
1-benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylaminocyclopropyl)pyrrolidine
(isomer A) was added 550 mg of 5% palladium-on-carbon, followed by
shaking in a hydrogen stream (4 kg/cm.sup.2) for 1.5 hours. The
catalyst was removed by filtration, and the solvent was removed by
evaporation under reduced pressure to give 343.6 mg (quantitative)
of the title compound as a brown oily substance.
[0197] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0198] 0.20-0.30 (1H, m), 0.75-0.95 (2H, m), 1.45 (9H, s),
1.55-1.75 (2H, m), 1.90-2.00 (1H, m), 2.60-2.70 (1H, m), 2.70-2.80
(1H, m), 2.90-3.00 (1H, m), 3.00-3.15 (2H, m), and 4.70-4.80 (1H,
brs).
Reference Example N
1-Benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine-2-thione
(Isomer B)
[0199] To 30 ml of a toluene solution of 1.534 g (4.86 mmol) of
1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one
(isomer B) was added 1.062 g (2.62 mmol) of a Lawson's reagent,
followed by stirring at 50 to 60.degree. C. for 1.5 hours. After
completion of the reaction, the reaction mixture was subjected to
silica gel column chromatography (hexane:ethyl acetate=7:3) to give
1.198 g (74.3%) of the title compound as a pale yellow solid.
[0200] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0201] 0.90-1.00 (1H, m), 1.00-1.10 (1H, m), 1.10-1.20 (1H, m),
1.35 (9H, s), 1.55-1.65 (1H, m), 2.40-2.50 (1H, m), 2.97 (1H, dd,
J=18.1, 6.3 Hz), 3.25-3.35 (2H, m), 3.52 (1H, dd, J=11.2, 6.8 Hz),
4.92 (1H, d, J=14.2 Hz), 5.01 (1H, d, J=14.2 Hz), 7.25-7.40 (5H,
m).
Reference Example O
1-Benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine (Isomer
B)
[0202] To 50 ml of an ethanol solution of 1.19 g (3.59 mmol) of
1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine-2-thione
(isomer B) was added 10 ml of Raney nickel, followed by stirring at
room temperature for 30 minutes. The insoluble matter was filtered
off, and the solvent was evaporated under reduced pressure.
Chloroform was added to the residue, and the mixture was washed
with 10% aqueous ammonia. The organic layer was dried over
anhydrous sodium sulfate, and the solvent was evaporated under
reduced pressure to give 929.0 mg (85.8%) of the title compound as
a pale yellow oily substance.
[0203] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0204] 0.85-0.95 (2H, m), 1.15-1.30 (1H, m), 1.38 (9H, s),
1.55-1.70 (2H, m), 2.05-2.25 (2H, m), 2.25-2.35 (1H, m), 2.50-2.75
(3H, m), 3.56 (1H, d, J=12.7 Hz), 3.60 (1H, d, J=12.7 Hz), and
7.20-7.40 (5H, m).
Reference Example P
1-Benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine
(Isomer B)
[0205] To 15 ml of a dichloromethane solution of 922.6 mg (3.06
mmol) of 1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)-pyrrolidine
(isomer B) was added 0.874 ml (6.12 mmol) of benzyl chloroformate
at room temperature, followed by stirring at the same temperature
overnight. To the reaction mixture was further added 0.502 ml (3.52
mmol) of benzyl chloroformate, followed by stirring for 2 days. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=7:3) to give 685.5 mg (64.8%) of the title compound as a
colorless oily substance.
[0206] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0207] 0.90-1.15 (3H, m), 1.43, 1.46 (9H, s each), 1.60-1.80 (2H,
m), 2.00-2.15 (1H, m), 2.20-2.30 (1H, m), 3.05-3.20 (1H, m),
3.30-3.50 (2H, m), 3.50-3.65 (1H, m), 5.10-5.20 (2H, m), and
7.25-7.40 (5H, m).
Reference Example Q
1-Benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylaminocyclopropyl)pyrrolidine
(Isomer B)
[0208] To 3 ml of a dichloromethane solution of 685.5 mg (1.98
mmol) of
1-benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine
(isomer B) was added 3 ml of trifluoroacetic acid under cooling
with ice, followed by stirring at room temperature for 1.5 hours.
After completion of the reaction, the solvent was evaporated under
reduced pressure, and toluene was added to the residue, followed by
evaporation to obtain a crude carboxylic acid.
[0209] To 20 ml of a 2-methyl-2-propanol solution of the resulting
crude carboxylic acid were added 0.411 ml (1.98 mmol) of
diphenylphosphoric acid azide and 0.399 ml (2.97 mmol) of
triethylamine, and the mixture was stirred at room temperature for
1.5 hours and then heated under reflux for 16 hours. After
completion of the reaction, the solvent was removed by evaporation
under reduced pressure, and ethyl acetate was added to the residue.
The mixture was washed successively with a 5% citric acid aqueous
solution, a saturated sodium carbonate aqueous solution, and a
saturated sodium chloride aqueous solution. The organic layer was
dried over anhydrous sodium sulfate, and the solvent was evaporated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane:ethyl acetate=7.3) to give 345.2 mg
(48.3%) of the title compound as a colorless oily substance.
[0210] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0211] 0.20-0.35 (1H, m), 0.75-0.85 (1H, m), 0.90-1.00 (1H, m),
1.40 (9H, s), 1.70-1.85 (2H, m), 1.95-2.10 (1H, m), 2.60-2.70 (1H,
m), 3.10-3.25 (1H, m), 3.30-3.40 (1H, m), 3.50-3.70 (2H, m),
4.50-4.65 (1H, brs), 5.05-5.20 (2H, m), and 7.25-7.40 (5H, m).
Reference Example R
3-(Cis-2-t-butoxycarbonylaminocyclopropyl)pyrrolidine (Isomer
B)
[0212] To 10 ml of an ethanol solution of 340.4 mg (0.94 mmol) of
1-benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylaminocyclopropyl)pyrrolidine
was added 350 mg of 5% palladium-on-carbon, and the mixture was
shaken in a hydrogen stream (3.5 kg/cm.sup.2) for 1.5 hours. The
catalyst was removed by filtration, and the solvent was evaporated
under reduced pressure to give 213.0 mg (99.7%) of the title
compound as a colorless solid.
[0213] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0214] 0.20-0.30 (1H, m), 0.75-1.00 (2H, m), 1.45 (9H, s),
1.60-1.80 (2H, m), 1.90-2.05 (1H, m), 2.60-2.80 (2H, m), 2.80-3.20
(3H, m), and 4.65-4.80 (1H, m).
Reference Example S
(1S,2R)-t-Butyl Cis-2-methoxycarbonylcyclopropanecarboxylate
[0215] To 120 ml of anhydrous tetrahydrofuran solution of 11.38 g
(79.0 mmol) of (-)-(1S,2R)-2-methoxycarbonylcyclopropanecarboxylic
acid were added 1.93 g (15.80 mmol) of dimethylaminopyridine and
22.41 g (102.67 mmol) of di-t-butyl dicarbonate at room
temperature, and the mixture was stirred at the same temperature
for 18 hours. After completion of the reaction, the solvent was
evaporated under reduced pressure, and ethyl acetate was added to
the residue. The mixture was washed successively with 0.5N
hydrochloric acid, water, and a saturated sodium chloride aqueous
solution. The organic layer was dried over anhydrous sodium
sulfate, and the solvent was evaporated under reduced pressure to
give 15.81 g (quantitative) of the title compound as a brown oily
substance.
[0216] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0217] 1.17 (1H, dt, J-8.3, 4.9 Hz), 1.44 (9H, s), 1.55-1.65 (1H,
m), 1.95-2.05 (2H, m), and 3.69 (3H, s).
Reference Example T
(1R,2S)-Cis-2-t-butoxycarbonylcyclopropanecarboxylic Acid
[0218] To 150 ml of a methanol solution of 15.81 g (79.0 mmol) of
(1S,2R)-t-butyl 2-methoxycarbonylcyclopropanecarboxylate was added
50 ml of an aqueous solution of 6.77 g (102.6 mmol) of potassium
hydroxide under ice-cooling, followed by stirring at room
temperature overnight. After completion of the reaction, the
solvent was removed by evaporation under reduced pressure. Water
was added to the residue, followed by washing with diethyl ether.
The aqueous solution was adjusted to a p of 2 to 3 with
concentrated hydrochloric acid and extracted with ethyl acetate.
The organic layer was dried over anhydrous sodium sulfate, and the
solvent was evaporated under reduced pressure to give 14.71 g
(quantitative) of the title compound as a pale yellow solid.
[0219] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0220] 1.25-1.35 (1H, m), 1.44 (9H, s), 1.60-1.65 (1H, m), and
2.00-2.10 (2H, m).
Reference Example U
Ethyl 3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]-3-oxopropionate
[0221] To 170 ml of an anhydrous tetrahydrofuran solution of 14.71
g (79.0 mmol) of (1R,2S)-2-t-butoxycarbonylcyclopropanecarboxylic
acid was added 16.49 g (90.6 mmol) of 1,1-carbonyldiimidazole under
cooling with ice, and the mixture was stirred at room temperature
for 1.5 hours. The solvent was removed by evaporation under reduced
pressure. To 60 ml of an anhydrous tetrahydrofuran solution of the
resulting residue was added 150 ml of an anhydrous tetrahydrofuran
solution of 197.5 mmol of previously prepared magnesium monoethyl
malonate, followed by stirring for 3 days. After completion of the
reaction, the solvent was evaporated under reduced pressure. Ethyl
acetate was added to the residue, and the mixture was washed
successively with 0.5N hydrochloric acid, a saturated sodium
hydrogencarbonate aqueous solution, and a saturated sodium chloride
aqueous solution. The organic layer was dried over an-hydrous
sodium sulfate, and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate=7:3) to give 18.53 g (91.8%)
of the title compound as a colorless oily substance.
[0222] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0223] 1.15-1.30 (4H, m), 1.42 (9H, s), 1.65-1.75 (1H, m),
2.00-2.10 (1H, m), 2.25-2.35 (1H, m), 3.50-3.65 (2H, m), and
4.15-5.25 (2H, m)
Reference Example V
Ethyl 3-[(1R,2S)-2-t-Butoxycarbonylcylcopropyl]acrylate
[0224] To 200 ml of a methanol solution of 18.48 g (72.1 mmol) of
ethyl 3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]-3-oxopropionate was
added 1.36 g (36.1 mmol) of sodium borohydride at -10.degree. C.,
followed by stirring at that temperature for 30 minutes. A
saturated ammonium chloride aqueous solution was added thereto, and
the reaction mixture was extracted with chloroform. The organic
layer was dried over anhydrous sodium sulfate, and the solvent was
evaporated under reduced pressure to give 18.62 g (quantitative) of
a crude alcohol as a colorless oily substance.
[0225] To 400 ml of a dichloromethane solution of 18.62 g (72.1
mmol) of the crude alcohol were added 20.10 ml (144.2 mmol) of
triethylamine and 7.25 ml (93.7 mmol) of methanesulfonyl chloride
under cooling with ice. After stirring the mixture at the same
temperature for 1.5 hours, 23.72 ml (158.6 mmol) of
1,8-diazabicyclo[5.4.0]-7-undecene was added thereto, followed by
stirring at room temperature for 15 hours. The solvent was
evaporated under reduced pressure, and chloroform was added to the
residue. The mixture was washed successively with 0.1N hydrochloric
acid, water, and a saturated sodium chloride aqueous solution. The
organic layer was dried over anhydrous sodium sulfate, and the
solvent was evaporated under reduced pressure to give 17.33 g
(quantitative) of the title compound as a yellow oily
substance.
[0226] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0227] 1.27 (3H, t, J=7.3 Hz), 1.25-1.35 (1H, m), 1.35-1.45 (1H,
m), 1.45 (9H, s), 1.90-2.05 (2H, m), 4.10-4.25 (2H, m), 5.98 (1H,
d, J=15.6 Hz), and 6.91 (1H, ddd, J=15.6, 8.8, 1.5 Hz)
Reference Example W
Ethyl
3-[(1R,2S)-2-t-Butoxycarbonylcyclopropyl]-3-nitroethylpropionate
[0228] To 150 ml of a nitromethane solution of 17.33 g (72.1
mmol)of ethyl 3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl)-acrylate
was added 14.47 ml (115.4 mmol) of tetramethylguanidine at room
temperature, and the mixture was stirred at 70.degree. C. for 3.5
hours. The solvent was evaporated under reduced pressure, and the
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=85:15) to give 18.95 g (87.2%) of the title
compound as a colorless oily substance.
[0229] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0230] 0.95-1.15 (2H, m), 1.25-1.35 (4H, m), 1.46 and 1.48 (9H, s
each), 1.65-1.80 (1H, m), 2.40-2.70 (2H, m), 2.70-2.85 (1H, m),
4.10-4.20 (2H, m), and 4.45-4.55 and 4.60-4.75 (2H, m each).
Reference Example X
3-[(1R,2S)-2-t-Butoxycarbonylcyclopropyl)pyrrolidin-2-one
[0231] To 600 ml of a methanol solution of 18.99 g (63.0 mmol) of
ethyl
3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]-3-nitroethylpropionate
were added about 5 g of 10% palladium-on-carbon, 7 g of 5%
palladium-on-carbon, and 51.67 g (819 mmol) of ammonium formate at
room temperature, and the mixture was stirred at the same
temperature for 4 hours. After completion of the reaction, the
solvent was evaporated under reduced pressure. Water was added to
the residue, followed by extraction with chloroform. The organic
layer was dried over anhydrous sodium sulfate, and the solvent was
evaporated under reduced pressure to give 14.67 g (85.8%) of a
crude amine.
[0232] A toluene solution (500 ml) of 14.67 g of the resulting
crude amine was heated at 110 to 120.degree. C. for 1.5 hours. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column chromatography
(chloroform:methanol=98:2) to give 10.38 g of a mixture of
3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidin-2-one and
3-[1R,2S)-2-t-butoxycarbonylcylcopropyl]-1-hydroxypyrrolidin-2-one
and 2.08 g of
3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]-1-hydroxypyrrolidin-2-
-one as colorless crystals.
[0233] To 100 ml of a solution of 1.85 g of the resulting
3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]-1-hydroxypyrrolidin-2-one
in a 3:1 mixed solvent of methanol and water was added 4.45 ml of a
titanium trichloride solution at room temperature while maintaining
the reaction mixture neutral by addition of a 1N sodium hydroxide
aqueous solution, followed by stirring at the same temperature for
1.5 hours. After completion of the reaction, water was added to the
reaction mixture, and the mixture was extracted with ethyl acetate.
The organic layer was dried over anhydrous sodium sulfate, and the
solvent was evaporated under reduced pressure to give 1.53 g
(88.4%) of 3-[(1R,2S)-2-t-butoxycarbonylc-
yclopropyl]pyrrolidin-2-one.
[0234] In the same manner, 7.30 g of
3-[(1R,2S)-2-t-butoxycarbonylcyclopro- pyl]pyrrolidin-2-one was
obtained from 9.49 g of the mixture of
3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidin-2-one and
3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]-1-hydroxypyrrolidin-2-one.
[0235] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0236] 0.95-1.10 (2H, m), 1.20-1.35 (1H, m), 1.45 (9H, s),
1.65-1.75 (1H, m), 2.05-2.60 (3H, m), 3.10-3.20, 3.20-3.30 (1H, m
each), 3.35-3.45, 3.55-3.65 (1H, m each), and 5.90-6.10 (1H,
m).
Reference Example Y
1-Benzyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidon-2-one
[0237] A solution (100 ml) of 8.816 g (39.1 mmol) of
3-[(1R,2S)-2-t-butoxycarbonylcylcopropyl]pyrrolidin-2-one in a 3:2
mixed solvent of tetrahydrofuran and dimethylformamide was added
dropwise to 20 ml of a suspension of 1.72 g (43.0 mmol) of sodium
hydride in dimethylformamide while cooling with ice, and the
mixture was stirred at room temperature for 1.5 hours. Then, 40 ml
of a tetrahydrofuran solution of 6.76 ml (58.7 mmol) of benzyl
chloride was added dropwise thereto, followed by stirring for 3
hours. After completion of the reaction, a saturated ammonium
chloride aqueous solution was added thereto, followed by
evaporation under reduced pressure. Water was added to the residue,
and the mixture was extracted with ethyl acetate. The organic layer
was washed with water and then with a saturated sodium chloride
aqueous solution. The organic layer was dried over anhydrous sodium
sulfate, and the solvent was evaporated under reduced pressure. The
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=7:3) to give 5.710 g (44.8%) of
1-benzyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopro-
pyl]pyrrolidin-2-one (isomer A.sup.1) as a colorless solid. Then,
the column was eluted with a 1:1 mixed solvent of hexane and ethyl
acetate to give 3.959 g (31.1%) of
1-benzyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl-
]pyrrolidin-2-one (isomer B.sup.1) as a pale yellow oily
substance.
[0238] Isomer A.sup.1:
[0239] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0240] 0.85-1.00 (2H, m), 1.10-1.20 (1H, m), 1.45 (9H, s),
1.65-1.75 (1H, m), 2.25 (1H, dd, J=16.1, 6.3 Hz), 2.35-2.45 (1H,
m), 2.50 (1H, dd, J=16.1, 8.8 Hz), 3.08 (1H, dd, J=9.8, 5.9 Hz),
3.43 (1H, dd, J=9.8, 7.8 Hz), 4.45 (1H, d, J=14.7 Hz), 4.46 (1H, d,
J=14.7 Hz), and 7.20-7.40 (5H, m)
[0241] Isomer B.sup.1:
[0242] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0243] 0.90-1.00 (1H, m), 1.00-1.05 (1H, m), 1.10-1.25 (1H, m),
1.37 (9H, s), 1.55-1.65 (1H, m), 2.33 (1H, dd, J=16.1, 7.3 Hz),
2.35-2.50 (1H, m), 2.67 (1H, dd, J=16.1, 8.3 Hz), 2.99 (1H, dd,
J=9.8, 6.3 Hz), 3.21 (1H, dd, J=9.8, 7.8 Hz), 4.40 (1H, d, J=14.7
Hz), 4.48 (1H, d, J=14.7 Hz), and 7.20-7.40 (5H, m)
[0244] [.alpha.].sub.D.sup.22+75.980 (c=1.045, CHCl.sub.3)
Reference Example Z
1-Benzyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidine-2-thione
(Isomer B.sup.1)
[0245] To 80 ml of a toluene solution of 3.999 g (12.69 mmol) of
1-benzyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]-pyrrolidin-2-one
(isomer B.sup.1) was added 2.769 g (6.85 mmol) of a Lawson's
reagent, and the mixture was stirred at 50 to 60.degree. C. for 1
hour and 40 minutes. After completion of the reaction, the reaction
mixture was subjected to silica gel column chromatography
(hexane:ethyl acetate=4:1) to give 4.044 g (96.2%) of the title
compound as a pale yellow solid.
[0246] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0247] 0.90-1.00 (1H, m), 1.00-1.10 (1H, m), 1.10-1.20 (1H, m),
1.35 (9H, s), 1.55-1.65 (1H, m), 2.40-2.55 (1H, m), 2.97 (1H, dd,
J=17.6, 6.4 Hz), 3.25-3.35 (2H, m), 3.52 (1H, dd, J=11.2, 7.8 Hz),
4.92 (1H, d, J=14.2 Hz), 5.01 (1H, d, J=14.2 Hz), and 7.25-7.40
(5H, m).
Reference Example AA
1-Benzyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidine
(Isomer B.sup.1)
[0248] To 60 ml of an ethanol solution of 4.040 g (12.19 mmol) of
1-benzyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]-pyrrolidine-2-thione
(isomer B.sup.1) was added 20 ml of Raney nickel, followed by
stirring at room temperature for 40 minutes. Any insoluble matter
was removed by filtration, and the solvent was evaporated under
reduced pressure. Chloroform was added to the residue, and the
mixture was washed with 10% aqueous ammonia. The organic layer was
dried over anhydrous sodium sulfate, and the solvent was evaporated
under reduced pressure to give 2.988 g (81.3%) of the title
compound as a colorless oily substance.
[0249] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0250] 0.85-1.00 (2H, m), 1.15-1.30 (1H, m), 1.38 (9H, s),
1.55-1.70 (2H, m), 2.00-2.25 (2H, m), 2.30 (1H, dd, J=9.3, 5.9 Hz),
2.50-2.65 (3H, m), 3.56 (1H, d, J=12.7 Hz), 3.60 (1H, d, J=12.7
Hz), and 7.20-7.35 (5H, m).
Reference Example BB
1-Benzyloxycarbonyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidine
(Isomer B.sup.1)
[0251] To 50 ml of a dichloromethane solution of 2.984 g 9.90 mmol)
o f 1-benzyl-3-[(1R, 2S )-2-t-butoxycarbonylcyclopropyl]pyrrolidine
(isomer B.sup.1) was added 2.83 ml (19.82 mmol) of benzyl
chloroformate at room temperature, and the mixture was stirred at
the same temperature for 14 hours. To the reaction mixture was
further added 1.98 ml (13.86 mmol) of benzyl chloroformate,
followed by refluxing for 2 hours. The solvent was evaporated under
reduced pressure, and the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=7:3) to give 2.188 g (64.0%)
of the title compound as a colorless oily substance.
[0252] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0253] 0.90-1.05 (2H, m), 1.05-1.15 (1H, m), 1.43 and 1.46 (9H, s
each), 1.60-1.80 (2H, m), 2.00-2.15 (1H, m), 2.20-2.30 (1H, m),
3.05-3.20 (1H, m), 3.30-3.40 (1H, m), 3.40-3.50 (1H, m), 3.50-3.65
(1H, m), 5.05-5.20 (2H, m), and 7.25-7.40 (5H, m).
Reference Example CC
1-Benzyloxycarbonyl-3-[(1S,2S)-2-t-butoxycarbonylaminocyclopropyl]pyrrolid-
ine (Isomer B1)
[0254] To 10 ml of a dichloromethane solution of 2.183 g (6.32
mmol) of
1-benzyloxycarbonyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidine
(isomer B.sup.1) was added 8 ml of trifluoroacetic acid under
cooling with ice, and the mixture was stirred at room temperature
for 1.5 hours. After completion of the reaction, the solvent was
evaporated under reduced pressure. Toluene was added to the residue
and evaporated under reduced pressure to obtain a crude carboxylic
acid.
[0255] To 60 ml of a solution of the resulting crude carboxylic
acid in 2-methyl-2-propanol were added 1.36 ml (6.32 mmol) of
diphenylphosphoric acid azide and 1.32 ml (9.48 mmol) of
triethylamine, and the mixture was stirred at room temperature for
1.5 hours and then heated under reflux for 35 hours. After
completion of the reaction, the solvent was evaporated under
reduced pressure. Ethyl acetate was added to the residue, and the
mixture was washed successively with a 5% citric acid aqueous
solution, a saturated sodium carbonate aqueous solution, and a
saturated sodium chloride aqueous solution. The organic layer was
dried over anhydrous sodium sulfate, and the solvent was evaporated
under reduced pressure. The resulting residue was purified by
silica gel column chromatography (hexane:ethyl acetate=7:3) to give
950.3 mg (41.7%) of the title compound as a colorless oily
substance.
[0256] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0257] 0.20-0.35 (1H, m), 0.75-0.90 (1H, m), 0.90-1.00 (1H, m),
1.40 (9H, s), 1.70-1.85 (2H, m), 1.95-2.10 (1H, m), 2.60-2.70 (1H,
m), 3.15-3.25 (1H, m), 3.30-3.40 (1H, m), 3.50-3.70 (2H, m),
4.50-4.65 (1H, brs), 5.05-5.15 (2H, m), and 7.25-7.40 (5H, m).
[0258] [.alpha.].sub.D.sup.23+36.820 (c=1.950, CHCl.sub.3)
Reference Example DD
3-[(1S,2S)-2-t-Butoxycarbonylaminocyclopropyl]pyrrolidine (Isomer
B.sup.1)
[0259] To 25 ml of an ethanol solution of 911.3 mg (2.53 mmol) o f
1-benzyloxycarbonyl-3-[(1S,2S)-2-t-butoxycarbonylaminocyclopropyl]pyrroli-
dine (isomer B.sup.1) was added 900 mg of 5% palladium-on-carbon,
and the mixture was shaken in a hydrogen stream (4.5 kg/cm.sup.2)
for 1.5 hours. To the reaction mixture was added 100 mg of 5%
palladium-on-carbon, followed by shaking in a hydrogen stream (4.0
kg/cm.sup.2) for 1 hour. The catalyst was removed by filtration,
and the solvent was removed by evaporation under reduced pressure
to give 572.2 mg (quantitative) of the title compound as a
colorless solid.
[0260] .sup.1H-NMR (CDCl.sub.3) .delta. ppm:
[0261] 0.20-0.30 (1H, m), 0.80-1.00 (2H, m), 1.45 (9H, s),
1.65-1.85 (2H, m), 2.y00-2.10 (1H, m), 2.60-2.70 (1H, m), 2.80-2.95
(1H, m), 2.95-3.10 (1H, m), 3.15-3.25 (2H, m), 4.75-4.95 (1H,
m).
[0262] The antimicrobial activity of the compound prepared in
Example 3 is shown in Table 1 below.
2TABLE 1 Antimicrobial Spectra Microorganism MIC (.mu.g/ml) E.
coil, NIHJ .ltoreq.0.003 S. flexneli, 2A 5503 .ltoreq.0.003 Pr.
vulgaris, 08601 0.05 Pr. mirabilis, IFO-3849 0.05 Ser. marcescens,
10100 0.10 Ps. aeruginosa, 32104 0.20 Ps. aeruginosa, 32121 0.10
Ps. maltophilia, IID-1275 0.05 S. aureaus, 209P .ltoreq.0.003 S.
epidermidis, 56500 0.006 Str. pyogenes, G-36 0.006 Str. faecalis,
ATCC-19433 0.025 S. aureus, 870307 0.025
[0263] Industrial Applicability
[0264] The compound according to the present invention exhibits
excellent activity and safety and is useful as an antimicrobial
agent.
* * * * *